Chapter 106. Plasma Cell Disorders (Part 1)

Harrisons Internal Medicine Chapter 106. Plasma Cell DisordersPlasma Cell Disorders: IntroductionThe plasma cell disorders are monoclonal neoplasms related to each other by virtue of their development from common progenitors in the B lymphocyte lineage. Multiple myeloma, Waldenströms macroglobulinemia, primaryamyloidosis (Chap. 324), and the heavy chain diseases comprise this group and may be designated by a variety of synonyms such as monoclonal gammopathies, paraproteinemias, plasma cell dyscrasias, and dysproteinemias. Mature B lymphocytes destined to produce IgG bear surface immunoglobulin molecules of both M and G heavy chain isotypes with both isotypes having identical idiotypes (variable regions). ...
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Chapter 106. Plasma Cell Disorders (Part 1) Chapter 106. Plasma Cell Disorders (Part 1) Harrisons Internal Medicine > Chapter 106. Plasma Cell Disorders Plasma Cell Disorders: Introduction The plasma cell disorders are monoclonal neoplasms related to each otherby virtue of their development from common progenitors in the B lymphocytelineage. Multiple myeloma, Waldenströms macroglobulinemia, primaryamyloidosis (Chap. 324), and the heavy chain diseases comprise this group andmay be designated by a variety of synonyms such as monoclonal gammopathies,paraproteinemias, plasma cell dyscrasias, and dysproteinemias. Mature Blymphocytes destined to produce IgG bear surface immunoglobulin molecules ofboth M and G heavy chain isotypes with both isotypes having identical idiotypes(variable regions). Under normal circumstances, maturation to antibody-secretingplasma cells is stimulated by exposure to the antigen for which the surfaceimmunoglobulin is specific; however, in the plasma cell disorders the control overthis process is lost. The clinical manifestations of all the plasma cell disordersrelate to the expansion of the neoplastic cells, to the secretion of cell products(immunoglobulin molecules or subunits, lymphokines), and to some extent to thehosts response to the tumor. Normal development of B lymphocytes is discussedin Chap. 308. There are three categories of structural variation among immunoglobulinmolecules that form antigenic determinants, and these are used to classifyimmunoglobulins (Chap. 308). Isotypes are those determinants that distinguishamong the main classes of antibodies of a given species and are the same in allnormal individuals of that species. Therefore, isotypic determinants are, bydefinition, recognized by antibodies from a distinct species (heterologous sera) butnot by antibodies from the same species (homologous sera). There are five heavychain isotypes (M, G, A, D, E) and two light chain isotypes (κ, λ). Allotypes aredistinct determinants that reflect regular small differences between individuals ofthe same species in the amino acid sequences of otherwise similarimmunoglobulins. These differences are determined by allelic genes; bydefinition, they are detected by antibodies made in the same species. Idiotypes arethe third category of antigenic determinants. They are unique to the moleculesproduced by a given clone of antibody-producing cells. Idiotypes are formed bythe unique structure of the antigen-binding portion of the molecule. Antibody molecules (Fig. 308-9) are composed of two heavy chains (molwt ~ 50,000) and two light chains (mol wt ~ 25,000). Each chain has a constantportion (limited amino acid sequence variability) and a variable region (extensivesequence variability). The light and heavy chains are linked by disulfide bonds andare aligned so that their variable regions are adjacent to one another. This variableregion forms the antigen recognition site of the antibody molecule; its uniquestructural features form a particular set of determinants, or idiotypes, that arereliable markers for a particular clone of cells because each antibody is formedand secreted by a single clone. Each chain is specified by distinct genes,synthesized separately, and assembled into an intact antibody molecule aftertranslation. Because of the mechanics of the gene rearrangements necessary tospecify the immunoglobulin variable regions (VDJ joining for the heavy chain, VJjoining for the light chain), a particular clone rearranges only one of the twochromosomes to produce an immunoglobulin molecule of only one light chainisotype and only one allotype (allelic exclusion). After exposure to antigen, thevariable region may become associated with a new heavy chain isotype (classswitch). Each clone of cells performs these sequential gene arrangements in aunique way. This results in each clone producing a unique immunoglobulinmolecule. In most cells, light chains are synthesized in slight excess, are secretedas free light chains by plasma cells, and are cleared by the kidney, but Electrophoretic analysis of components of the serum proteins permitsdetermination of the amount of immunoglobulin in the serum (Fig. 106-1). Theimmunoglobulins move heterogeneously in an electric field and form a broad peakin the gamma region. The γ globulin region of the electrophoretic pattern isusually increased in the sera of patients with plasma cell tumors. There is a sharpspike in this region called an M component (M for monoclonal). Less commonly,the M component may appear in the β2 or α2 globulin region. The antibody mustbe present at a concentration of at least 5 g/L (0.5 g/dL) to be detectable by thismethod. This corresponds to ~109 cells producing the anti ...